Honokiol induces proteasomal degradation of AML1-ETO oncoprotein via increasing ubiquitin conjugase UbcH8 expression in leukemia.

Abstract

AML1-ETO is the most common oncoprotein leading to acute myeloid leukemia (AML), in which 5-year survival rate is only about 30%. However, currently there are no specific therapies for AML patients with AML1-ETO. Here, we report that AML1-ETO protein is rapidly degraded by Honokiol (HNK), a natural phenolic compound isolated from the plant Magnolia officinalis. HNK induced the degradation of AML1-ETO in a concentration- and time-dependent manner in leukemic cell lines and primary AML blasts with t(8;21) translocation. Mechanistically, HNK obviously increased the expression of UbcH8, an E2-conjugase for the degradation of AML1-ETO, through triggering accumulation of acetylated histones in the promoter region of UbcH8. Knockdown of UbcH8 by small hairpin RNAs (shRNAs) prevented HNK-induced degradation of AML-ETO, suggesting that UbcH8 plays a critical role in the degradation of AML1-ETO. HNK inhibited cell proliferation and induced apoptotic death without activation of caspase-3, which was reported to cleave and degrade AML1-ETO protein. Thus, HNK-induced degradation of AML1-ETO is independent of activation of caspase-3. Finally, HNK reduced the angiogenesis and migration in Kasumi-1-injected zebrafish, decreased xenograft tumor size in a xenograft leukemia mouse model, and prolonged the survival time in mouse C1498 AML model. Collectively, HNK might be a potential treatment for t(8;21) leukemia by targeting AML1-ETO oncoprotein.

• Authors: Bin Zhou, Haiying Li, Chongyun Xing, Haige Ye, Jianhua Feng, Jianbo Wu, Zhongqiu Lu, Jing Fang, Shenmeng Gao
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 128 Pg. 12-25 (Mar 15 2017) ISSN: 1873-2968 [Electronic] England
• PMID: 28043811 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• AML1-ETO fusion protein, human
• Antineoplastic Agents, Phytogenic
• Biphenyl Compounds
• Core Binding Factor Alpha 2 Subunit
• Lignans
• Oncogene Proteins, Fusion
• RUNX1 Translocation Partner 1 Protein
• honokiol
• UBE2L6 protein, human
• Ubiquitin-Conjugating Enzymes
• Proteasome Endopeptidase Complex

Topics

• Acetylation
• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis
• Biphenyl Compounds (pharmacology)
• Cell Line, Tumor
• Core Binding Factor Alpha 2 Subunit (metabolism)
• Embryo, Nonmammalian (blood supply, drug effects)
• Humans
• Leukemia, Myeloid, Acute (drug therapy, metabolism, pathology)
• Lignans (pharmacology)
• Male
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Neovascularization, Physiologic (drug effects)
• Oncogene Proteins, Fusion (metabolism)
• Promoter Regions, Genetic
• Proteasome Endopeptidase Complex (metabolism)
• RUNX1 Translocation Partner 1 Protein
• Ubiquitin-Conjugating Enzymes (genetics, metabolism)
• Zebrafish